PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (PH) is a multifactorial disease characterized by progression to heart failure and increased morbidity despite existing therapies. Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct subtype of PH characterized by diffuse in situ thromboembolic vascular remodeling of pulmonary arterioles. Current concepts regarding the pathophysiology of CTEPH include contributions of hyperactive coagulation, insufficient anticoagulation, and impaired thrombus resolution. However, no unifying mechanism has been identified to explain the concomitant diffuse arteriopathy observed in areas not implicated as the site of initial vascular injury. Based on preliminary data from the Maron Pulmonary Vascular Research Laboratory, the Cas-L protein, NEDD9, has emerged as an unanticipated mediator of thrombosis and vascular fibrosis in human pulmonary artery endothelial cells in vitro and in both rodent models of pulmonary arterial hypertension (PAH) and patients afflicted with PAH in vivo. We hypothesize that NEDD9 contributes to both (1) the thrombogenic pathophenotype in CTEPH by disrupting the homeostasis between thrombosis and fibrinolysis resulting in increased platelet-endothelial cell adhesion and (2) the angioproliferation and vascular fibrosis observed in CTEPH by promoting cell proliferation and collagen deposition. The purpose of this proposal is to use cell biology and proteomics to determine the mechanism by which NEDD9 contributes to endothelial dysfunction and cell proliferation in vitro and clinically translate these findings by studying blood, endothelial cells, and surgically extracted thromboemboli from CTEPH patients. As part of the research training program, the principal investigator will learn to use conventional methods in cell biology, proteomics, and transgenic murine models, and obtain a Certificate in Applied Biostatistics through Harvard Catalyst. This research project will be performed under the guidance of well-established investigators in pulmonary vascular disease with additional advice from experts in vascular biology and PH.